DESCRIPTION: Cocaine addiction continues to be a medical problem with profound social and financial cost. Those seeking treatment for their addiction find it extremely difficult to abstain from psychostimulant use and relapse to drug taking behavior is the norm. Our long term objective is to understand the neurobiology of cocaine abuse and define the neurotransmitter interactions that influence drug taking and relapse. We expect that a clearer understanding of these basic brain mechanisms will be useful in the development of a medication that could effectively suppress cravings for cocaine. Our working hypothesis is that drugs which act specifically at GABA synapses produce behaviorally specific effects on cocaine reinforcement. Several models will be used to assess the efficacy and specificity of the anti-cocaine effects of baclofen. We have previously shown that baclofen and other GABAB agonists have powerful and apparently specific effects on cocaine self-administration in rats. Preliminary clinical data (reported by others) have also been encouraging. In an effort to characterize the pharmacological specificity of this effect, we will investigate whether the GABAB antagonist CGP56433 attenuates baclofen-induced suppression of cocaine intake. A further aim is to identify the site(s) of action of the GABA modulation of cocaine reinforcement. The effects of microinjections of baclofen into defined brain areas on cocaine self-administration behavior and other measures of performance will be assessed. A progressive ratio schedule and other procedures designed to assess changes in the reinforcing efficacy of cocaine will be used. We have recently developed a procedure that produces binge-type patterns of cocaine self-administration in the rat. Experiments will examine the effect of various treatment regimens of baclofen in this model of late stage addiction. The degree to which either IP or intracerebral injections of baclofen affect heroin self-administration will also be assessed.